High concentration medicament and polymer coated device for passive diffusional medicament delivery

ABSTRACT

The present invention relates to a catheter with an expandable distal end for delivering one or more medicaments. The catheter also has a means for controlling or manipulating the expandable distal end to expand and contract into various configurations to apply pressure and achieve good contact against the walls of structures into which it is advanced. The distal end of the catheter is processed by a specific method of manufacturing whereby the expandable distal end is coated with one or more layers of a polymer wherein the surface layer of which coating carries one or more medicaments at very high concentration and zero or more excipients to facilitate the diffusional penetration of the medicaments into contacted tissues.

PRIOR APPLICATIONS

This application is a continuation-in-part of application Ser. No. 09/997,855 filed on Nov. 29, 2001.

BACKGROUND OF THE INVENTION

Cardiovascular disease is commonly accepted as being one of the most serious health risks facing our society today. Diseased and obstructed coronary arteries can restrict the flow of blood and cause tissue ischemia and necrosis. After over two decades of investigation, the exact etiology of sclerotic cardiovascular disease is still in question, the treatment of narrowed coronary arteries is more defined. Surgical construction of coronary artery bypass grafts (CABG) is often the method of choice when there are several diseased segments in one or multiple arteries. Open heart surgery is, of course, very traumatic for patients. In many cases, less traumatic, alternative methods are available for treating cardiovascular disease percutaneously. These alternate treatment methods generally employ various types of percutaneous transluminal angioplasty (PTCA) balloons or excising devices (atherectomy) to remodel or debulk diseased vessel segments. A further alternative treatment method involves percutaneous, intraluminal installation of expandable, tubular stents or prostheses in sclerotic lesions.

A recurrent problem with the previous devices and PTCA procedures is their failure to maintain patency due to the growth of injured vascular tissue. This is known as “restenosis” and may be a result of the original injury to the vessel wall occurring during the angioplasty procedure. Pathologically restenosis represents a neointimal proliferative response characterized by smooth muscle cell hyperplasia that results in reblockage of the vessel lumen necessitating repeat PTCA procedures in up to 35-50% of all cases. It has been generally accepted that certain therapeutic agents or medicaments may be capable of selectively inhibiting the growth of these hyperproliferating smooth muscle cells and thereby reduce the rate of restenosis after the primary interventional procedure.

Heretofore, various devices have been disclosed which may be used to deliver a therapeutic agent or medicament to a blood vessel while undergoing angioplasty. Balloon angioplasty catheters have been used to place and deliver various therapeutic agents or medicaments within human vessels. For example, in U.S. Pat. Nos. 5,112,305, 5,746,716, 5,681,281, 5,873,852, 5,713,863 and 6,102,904 disclose and claim a balloon catheter system with various injector plates mounted on the balloon for delivering a drug into an arterial segment.

Alternatively a standard angioplasty balloon may be coated with a substrate or polymeric material which either incorporates, or is then used to bond, certain medicaments or theraputic agents. These agents are then delivered to the desired therapeutic site by inflation of the balloon and diffusion of the medicament or therapeutic agent into the vessel wall. Only limited quantities of therapeutic agents can be delivered because of “wash-out” of the drug into the circulation during balloon placement and due to the limited time the inflated balloon can be left in place due to ischemia caused by the balloon.

In addition, previously disclosed methods of delivering drug to a site of treatment are described which utilize iontophoretic or electrophoretic means as disclosed in U.S. Pat. No. 5,499,971. Using these iontophoretic or electrophoretic means passive diffusion of the drug or medicament is enhanced by placing the medicament or therapeutic agent in close proximity to the site of treatment and then using electrical energy to augment delivery of the drug into the tissues or cells. These methods generally place the drug inside a balloon mounted distally on a catheter whereby the balloon is composed of a semi-porous material through which the drug can diffuse.

Additional devices have been disclosed which attempt to improve the depth of penetration into tissue by pressure driving a solution of the drug into the vessel wall through small orifices in the balloon material. There-is, however, some evidence that high pressure “jetting” of a drug solution out of small pores close to the vessel lumen can in fact cause vessel wall injury. The development of double skinned, microporous (or weeping) balloons obviated this “jetting” effect to some extent, but diffusion of the drug into the vessel wall is still slow, and much of the drug can be lost through subsequent “washout effects”. This method leads to limited amounts of drugs or therapeutic agents delivered to the tissues or cells. Furthermore, in all of these methods the balloon must be expanded and thereby restricts blood flow to the distal arterial segments while the balloon is in the expanded configuration thus limiting the time the drug delivering balloon can be clinically utilized.

There are also several disadvantages to using either a stent or balloon catheter to deliver a therapeutic agent or medicament to a vascular segment. Regarding the therapeutic agent eluting stents, once the stent is deployed, there is no means outside of invasive surgical excision, to remove the eluting stent from the vascular segment. Therefore, stents or implanted prostheses with therapeutic agent eluting properties must be precisely calibrated to deliver an exact quantity of the therapeutic agent or medicament to the vascular segment upon stent deployment. Balloon catheters employed to deliver a therapeutic agent or medicament to a vascular segment have limitations including potential balloon rupture and ischemia due to balloon inflation limiting distal blood flow to the artery. This leads to tissue ischemia and potential necrosis. Even “perfusion” type angioplasty balloons used to delivery a therapeutic agent or medicament to the affected artery provide far less than physiological blood flow during balloon inflation and dwell times are limited by ischemia and tissue necrosis.

Additional devices have been disclosed which utilize catheter based multiple injecton ports to inject the drug directly into the vessel walls. Disadvantages of this system include potential injury to vessel walls, non-uniform drug delivery and the requirement that the drug must be carried either in the solubilized form or in fine suspensions which is a particular problem for drugs that are not water-soluble).

Recent studies have demonstrated the effectiveness of a number of agents (e.g., paclitaxel, rapamycin, Actinomycin D) to prevent unwanted cellular proliferation. These agents have proven efficacy in the treatment of cancer transplant rejection and restenosis following angioplasty. A major advantage of these agents is their high lipid solubility that causes tissue levels of these agents to remain high for an extended period of time since they cannot be rapidly cleared. However, the delivery of these lipophillic medicaments generally present formulation and transport challenges in aqueous media. Furthermore, they are less likely to permeate across hydrophilic boundaries and cell membranes into tissue.

In general, it is an object of this present invention to provide a catheter coated with a polymer containing or carrying one or more medicaments at sufficient concentration to be capable of delivering, by passive diffusion means, the medicament(s) to the vessel segment or obstruction.

In general, it is an object of this present invention to provide a catheter system whereby the catheter can be applied in pressurized contact with the vascular surface and remain in place for sufficient time without ischemic effect to facilitate the release of medicaments present from the high concentration in the polymer present on a portion of the catheter.

In general, it is an object of this present invention to provide a method whereby the medicament is presented in the right physical-chemical form and in sufficient concentration to be released from the polymer and transported into the surrounding tissues at therapeutic levels. The delivery of the medicaments can be without any excipients or with one or more excipients chosen to alter drug solubility or to aid in tissue penetration. The excipients can be charged or nonionic surfactants, polyelectrolytes, lipids, fatty acids or esters, liposomes or other solubility-altering entities.

Another object of the invention is to provide a method to deliver high concentrations of agents that are poorly soluble or insoluble in aqueous media to selected sites in the body including arteries, veins or other tubular structures, prosthetic devices such as grafts, and tissues such as, but not limited to, brain, myocardium, colon, liver, breast and lung or to other abnormal or pathological tissues such as tumors or wounds.

Another object of the invention is to provide an apparatus and a method to deliver a wide range of medicaments with different degrees of solubility, molecular sizes and chemical structures These medicaments can be charged or neutral. The medicaments can include, but not exclusively, genetic agents

Another object of the invention is to provide an apparatus and a method that can control and direct the active release or diffusion of a medicament or therapeutic agent to minimize potential systemic effects and promote and maximize the delivery of the medicament or therapeutic agent into the surrounding tissue

Another object of the invention is to provide an apparatus and a method to promote and maximize the penetration of a medicament or therapeutic agent into the surrounding tissues uniformly throughout the diseased area and to facilitate the binding to the tissue and thus promote a therapeutic effect.

Another object of the invention is to provide a apparatus and method that can promote the active release or diffusion of a medicament or therapeutic agent while simultaneously dilating an obstruction within a blood vessel or organ.

Another object of the invention is to provide an apparatus and method that can promote the diffusion of a medicament or therapeutic agent while simultaneously allowing perfusion of blood or liquid to occur through the apparatus delivering the medicament or therapeutic agent.

SUMMARY OF THE INVENTION

The present invention relates to a catheter with an expandable distal end. The catheter is manufactured with materials of construction that has a means for controlling or manipulating the expandable distal end to expand and contract into various configurations.

The distal end of the catheter is processed by a specific method of manufacturing whereby the expandable distal end is coated with one or more layers of a polymer at least one layer of which coating contains or retains one or more medicaments and zero or more excipients to facilitate delivery of the medicaments into target tissue.

The successful diffusion of the desired medicaments out of or off the polymer coating and into surrounding tissue in this invention, depends on many factors. Diffusion is dependent on the solubility of the medicament in the tissue at the interface as well as the surface characteristics, rough or smooth, of the coating and the pressure of the catheter at the surface to gain contact and exclude the hydrophillic barrier of a layer of liquid. Other factors affecting migration and tissue penetration include the selection of the polymer and its chemical and physical characteristics, the selection of any excipients to alter solubility or aid in tissue penetration, and the residence time for tissue contact.

The present invention relates to the delivery of medicaments within the body of a patient. The invention uses high concentration diffusion mediated drug delivery with a specially designed catheter. The catheter has a metal mesh on its distal end that expands against a solid, tubular or hollow structure. The mesh is coated with one or more layers of polymer at least one layer of which contains at least one drug or medicament and zero or more excipients.

The polymer used in the present invention is a hydrophilic polyurethane that exhibits moderate swelling in aqueous media. It is anticipated by the Applicants that other hydrophilic polymers having similar properties as the polyurethane polymer can function with the present invention. The polymer used in the current invention possesses the following characteristics. It forms strong adhesion or cohesion with the catheter metal surface. The adhesion or cohesion must sustain repeated contraction and expansion of the catheter mesh during application. Furthermore, the polymer must possess certain tensile and mechanical properties that preserve the coating integrity during the contraction and expansion operations of the catheter mesh.

In the present invention the ratio of drug to polymer at the surface is much higher than prior, traditional drug polymeric drug delivery systems in which the polymer exerts some control of delivery. In one embodiment the medicament paclitaxel is incorporated only in the final topcoat of a polymer/drug combination at a range of 60-90/40-10 weight/weight drug to polymer ratio of solids, with a preferred 80/20 weight/weight drug to polymer ratio or solids. This composition is applied with a solvent or mixture of solvents chosen to be sufficiently rapidly evaporating that during deposition and drying the drug does not penetrate significantly into the base coats. For example, a solvent consisting of an ethanol/H₂O can be used for the base coating and then tetrahydrofuran (THF) and toluene as a solvent for the heavily laden top coating. Using the same polymer for each coating, the base coating will resist dissolving and inhibit migration of the medicament from the heavily laden top coating. The mixed solvent is chosen to be of intermediate dissolution capability for both polymer and medicament so as to minimize penetration-migration into the polymer base coats. The polymer structure is also chosen to be sufficiently lipophobic that crystalline paclitaxel is excluded or blooms during drying. Further crystallization occurs upon flexing of the catheter. Because it is in crystalline form and a very hydrophobic medicament there is minimal loss of paclitaxel into the bloodstream during placement in vascular applications. Like drugs of lipophillic nature would behave similarly, but for more soluble drugs, excipients including materials that encapsulate the medicament would be used.

The chemical characteristics of a polymer, such as the degree of hydrophilicity, and physical characteristics such as mechanical strength, may be also be controlled by the chemical structure, crosslinking and molecular weight range. The flexibility to adjust the chemical composition of a suitable polymer makes it possible to carry a wide range of medicaments of different chemical and physical properties. Other specific polymers and polymer classes that have necessary physical properties and form water-filled porous structures will be obvious to those skilled in the art.

Conventional coating methods can be used to apply a viscous polymer solution, melt or suspension to the catheter surface to form a thin layer of coating. The polymer coats may be dried in air or dried with heating or coagulated and precipitated in the presence of a non-solvent. The present invention requires multiple coating layers with the same or different polymer. Each layer may or may not contain medicaments but the final coating contains a very high proportion of medicament on a solids weight basis. In the event a multiple layer coating is employed with a hydrogel or other similar type polymer, the introduction of water to completely coagulate the copolymer is the final step. Other methods of deposition or coating such as spraying, application of melts or powders with annealing will be well-known to those skilled in the art.

The delivering of medicaments by the present invention and methods generally comprises the steps of advancing a catheter or medical device generally including a distal expansion member and advancing the expansion member to an obstruction within a vessel or to the desired site of treatment. At this time the clinician applies forces on the expansion member causing the expansion member to become fully expanded wherein the expansion member contacts the surrounding tissue. Prolonged strong contact between the high concentration of the medicament including crystals of the medicament on the surface of the expansion member and the tissue being treated results in some dissolution and diffusion of the medicament into the lipid components of the tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side-elevational view partially in section of a medicament delivery device incorporating a polymer coating carrying a therapeutic agent.

FIG. 2 is a cross-sectional view taken along the line 2-2 of FIG. 1.

FIG. 3 is a cross-sectional view taken along the line 3-3 of FIG. 1.

FIG. 4 is a cross-sectional view taken along the line 4-4 of FIG. 1.

FIG. 5 is a cross-sectional view taken along the line 6-6 of FIG. 1.

FIG. 6 is a greatly enlarged view of a portion of the dilatation and medicament delivery device in a partially expanded state.

FIG. 7 is a side-elevational view of the distal extremity of the device shown in FIGS. 1-6 showing the distal extremity with the expansion member in an expanded condition showing the polymer with therapeutic agents or medicaments coated on the distal expansion member.

FIG. 8 is a representation of the multi-layered polymer coating that carries a very high concentration of therapeutic agents or medicaments and includes exposed crystalline therapeutic agents or medicaments on the surface of the distal expansion member.

FIG. 9 is a greatly enlarged view of a portion of the polymer with therapeutic agents of medicaments coated on the distal expansion member.

FIG. 10 is a greatly enlarged view of a portion of the multilayer coating the carries a very high concentration including exposed crystalline therapeutic agents of medicaments on the surface.

DETAILED DESCRIPTION OF THE DRAWINGS

In general, the present invention relates generally to devices that are used to dilate and dispense a medicament or therapeutic agent to an obstruction within a stenotic segment of a vessel or other tubular structure. The device is comprised of a cylindrical expansion member to be disposed in an obstruction in a vessel carrying flowing blood. The cylindrical expansion member has first and second ends and an intermediate portion between the first and second ends. The cylindrical expansion member also has a flow passage extending therethrough with a diameter and a longitudinal central axis. The diameter of the flow passage is a variable with movement of the first and second ends relative to each other along the longitudinal central axis from a diametrically contracted position to a diametrically expanded condition. The cylindrical expansion member is comprised of a plurality of flexible elongate elements each of which extends helically about the longitudinal extending central axis. The flexible elongate elements are coated with a polymer carrying a therapeutic agent, medicaments, drugs, pharmaceuticals, plasmids, genes, double and single stranded DNA double and single stranded RNA or other agents. For the purposes of this application, the terms polymer carrying a medicament or therapeutic agent, drugs, pharmaceuticals, plasmids, genes or other agents, will be used to encompass all the particular agents described herein. It is also contemplated that the polymer carrying medicament or therapeutic agent may be incorporated with a non-medicament substrate that has been previously or simultaneously coated on the flexible elongate elements.

Means are provided for engaging the first and second ends of said cylindrical expansion member for retaining said first and second ends in contracted positions. Means are provided for causing relative axial movement of the first and second ends towards each other to cause the intermediate cylindrical portion of the expansion member to contract longitudinally and to expand diametrically by causing the flexible elongate elements in the intermediate portion of the cylindrical member to move closer to each other expanding the diametric dimensions of the cylindrical expansion member thereby allowing it to contact the vessel wall and enable it to dilate an obstruction within the vessel. Flexible elongate elements at the first and second ends of the cylindrical expansion member remain contracted around and within first and second means and are thereby prevented from moving closer which maintains spacing between the flexible elongate members so that blood in the vessel can continue to flow through the first and second ends and through the flow passage in the cylindrical expansion member while the cylindrical expansion member is in engagement with vessel wall and dilating an obstruction within the vessel.

More in particular as shown in FIGS. 1-6 of the drawings, the mechanical dilation and medicament delivery device 11 shown therein consists of a first or outer flexible elongate tubular member 12 having proximal and distal extremities 13 and 14 with the outer flow passage 16 extending from the proximal extremity 13 to the distal extremity 14. A second or inner flexible tubular member 21 is coaxially and slidably disposed within the outer flow passage 16 of the first or outer flexible elongate tubular member 12 and is provided with proximal and distal extremities 22 and 23 with a lumen 24 extending from the proximal extremity 22 to the distal extremity 23. The flexible elongate elements of the dilating member are made of a metallic material such as stainless steel, Elgiloy® or other biocompatible metal.

A guide wire 26 of a conventional type is adapted to be introduced through the lumen 24 in the inner flexible elongate tubular member for use in guiding the mechanical dilatation and medicament delivery device 11 as a over-the-wire design as hereinafter described. The guide wire 26 can be of a suitable size as for example 0.010″-0.035″ and can have a suitable length ranging from 150 to 300 centimeters. For example, the first or outer flexible elongate tubular member 12 can have an outside diameter of 0.6-3 millimeters with a wall thickness of 0.12 millimeters to provide a flow passage 16 of 0.75 millimeters in diameter. Similarly, the second or inner flexible elongate tubular member 21 can have a suitable outside diameter as for example 0.6 millimeters with a wall thickness of 0.12 millimeters and an inner lumen 24 of 0.45 millimeters in diameter. The flexible elongate tubular members 12 and 21 can be formed of a suitable plastic as for example a polyimide, polyethylene, Nylon or polybutylteraphthalate (PBT).

In accordance with the present invention an essentially cylindrically shaped expansion member 31 is provided which has a first or proximal end 32 and a second or distal end 33 with a central or inner flow passage 34 extending from the proximal end 32 to the distal end 33 along a longitudinally extending central axis and has a diameter which is a variable as hereinafter described. The cylindrically shaped expansion member 31 is comprised of a plurality of flexible elongate elements or filaments 36 each of which extends helically about the longitudinally extending central axis. The flexible elongate elements 36 are formed of suitable materials which can be utilized in the human blood as for example stainless steel, Nitinol, AerMet®, Elgiloy® or certain other metal fibers. The flexible elongate elements 36 can have a suitable diameter as for example 0.001 to 0.010 inches or can be configured as a round, elliptical, flat or triangular wire ribbon. A plurality of the flexible elongate elements 36 have a first common direction of rotation about the central axis as shown in FIGS. 1 and 6 are axially displaced relative to each other and cross a further plurality of the flexible elongate elements 36 also axially displaced relative to each other but having a second common direction of rotation opposite to that of the first direction of rotation to form a double helix or braided or mesh-like cylindrical expansion member with the crossing of flexible elongate elements 36 occurring in the area of contact between the flexible elongate elements to form openings or interstices 37 therebetween. Thus the flexible elongate elements 36 form an expansion member 31 which provides a central or inner flow passage 34 which is variable in diameter upon movement of the first and second ends of the expansion member 31 relative to each other along the longitudinally extending central axis.

Means is provided for constraining the first and second or proximal and distal ends 32 and 33 of the expansion member 31 and consists of a first or proximal collar 41 and a second or distal collar 42. The first and second collars 41 and 42 are formed of a suitable material such as a polyimide.

Typically the distance between the first and second collars 41 and 42 can range from between 5 to 150 millimeters. Typically the distal end 23 of the second or inner flexible elongate tubular member 21 extends approximately 5-170 millimeters beyond the distal extremity 14 of the first or outer flexible elongate tubular member 12.

It can be seen that by moving the first or outer flexible elongate tubular member 12 and the second inner flexible elongate tubular member 21 axially with respect to each other, the first and second ends of the expansion member 31 are moved towards each other causing the elongate elements or filaments 36 of an intermediate portion of the cylindrical expansion member between the first and second ends to move closer to each other to cause these flexible elongate elements to move into apposition with each other and to expand in a first radial direction the intermediate portion of the cylindrical expansion member 31 (FIG. 6) and to cause the diameter of the central flow passage 34 to increase. The portions of the expansion member 31 immediately adjacent the first and second collars 41 and 42 remain restrained by the collars 41 and 42 causing the flexible elongate elements 36 immediately adjacent to the collars 41 and 42 to curve conically toward and remain crossed and unable to come into close apposition and thereby provide openings or interstices 37 therebetween, which remain relatively constant in shape and size so that blood can flow from the first and second ends 32 and 33 through the central or inner flow passage 34 as hereinafter described.

The essentially cylindrical shape of the expansion member when expanded in a radial direction provides an enlarged surface of contact between the expansion member and the vessel wall or obstruction. This enlarged surface of contact enables the cylindrical expansion member to deliver an increased amount of medicament or therapeutic agent which is incorporated within and upon the polymer coated on the surface of the flexible elongate elements that comprise the expansion member. This delivery of medicament or therapeutic agent may be by the various well known means previously described: active diffusion and pressure against and superficially into the tissue.

One example of the means provided in the mechanical dilation and medicament delivery device 11 for causing relative movement between the first or outer flexible elongate tubular member 12 and the second or inner flexible elongate tubular member 21 and consists of a linear movement mechanism 46. The linear movement mechanism 46 includes a Y-adapter 49 that is provided with a central arm 51 having a lumen 52 through which the second or inner flexible elongate tubular member 21 extends.

It should be appreciated that even though one particular linear movement mechanism 46 has been provided for advancing and retracting the flexible elongate members 12 and 21 with respect to each other, other mechanisms also can be utilized if desired to provide such relative movement. Other possible designs that could be employed are scissors-jack, rachet-type or straight slide mechanisms.

As shown in FIG. 7 and enlarged in FIG. 9, the distal extremity of the device shown in FIGS. 1-6 is an expansion member or mesh 31 in an expanded condition with a the therapeutic agents or medicaments 40 incorporated within a polymer substrate 43 and coated on the flexible elongate elements 36 of the distal expansion member 31. The polymeric coating on the expansion member terminates at an intermediate position 42 a, 1-5 mm distance from the ends of the expansion member or collar 41. Thus when the distal cylindrical expansion member is fully expanded, blood or fluid may still freely flow into the proximal end of the cylindrical expansion member 43 a, through the cylindrical expansion member and out the distal end of the expansion member 44 a. Thus perfusion of blood or liquid is permitted into the distal vessel or organ even when the expansion member is fully expanded against the wall of the vessel or tubular structure for prolonged periods of time. Alternatively, the polymeric coating may cover only the individual wires and not cover the interstices of the distal cylindrical expansion member. This would allow both distal and sidebranch perfusion to occur despite full expansion of the distal cylindrical expansion member against the vessel wall for prolonged periods of time. When the polymer coated distal cylindrical expansion member 35 is fully expanded it is almost a solid tubular mass which reduces area of the interstices or openings 37 and maximizes the medicament coated flexible elongate elements for intimate pressurized contact with the vessel walls. FIG. 9 demonstrates a greatly enlarged view of a portion of the polymer with therapeutic agents of medicaments coated on the distal expansion member.

Now referring to FIG. 8, the polymer and medicament distal expansion member 35 is fully expanded it is almost a solid tubular mass which reduces area of the interstices or openings 37 and maximizes the medicament coated flexible elongate elements for intimate pressurized contact with the vessel walls. The embodiment of FIGS. 8 and 10 comprises a coated distal expansion member 35 including a multi-layered polymer or substrate coating 43 that carries a base coat 82 of pure substrate 43 or medicament incorporated polymer 47 together with a top layer 80 of polymer incorporating the therapeutic agent of medicament 40 in a very high concentration 48. The top layer 80 also can be disposed with a solvent that rapidly evaporates but is also a poor solvent for the polymer/medicament combination and does not significantly penetrate the base coat. For example, A solvent consisting of a ethanol/H₂O can be used for the base coating and then tetrahydrofuran (THF) and toluene as a solvent for the heavily laden top coating. Using the same polymer for each coating, the base coating will resist dissolving and inhibit migration of the medicament from the heavily laden top coating. In addition, the evaporation of the solvent can leave exposed crystallized therapeutic agents or medicaments 38 on the surface of the coated expansion member 35. FIG. 10 demonstrates a greatly enlarged view of a portion of the multilayer coating the carries a very high concentration including exposed crystalline therapeutic agents of medicaments on the surface. There is minimal loss of a lipophilic therapeutic agent or medicament 40 from the top layer due to low aqueous solubility. For more soluble medicaments a secondary coating (not shown) may be applied to retard the loss of previously coated drugs or medicaments 40 and excipients 39 into the bloodstream or tissues which may occur prior to the delivery of the drug or medicaments 40 at the desired tissue site.

Once the site of obstruction or treatment is reached and the distal cylindrical expansion member 31 is expanded, the expansion member is in physical contact with the surrounding tissue or vessel wall. The distal expansion member 31 of the catheter is coated with one or more layers of a polymer material or similar substrate 43, into and onto which are encapsulated one or more medicaments or therapeutic agents 40 and zero or more excipients to alter the solubility of the medicaments or their tissue penetration. These excipients 39 may include by example, neutral or charged lipids, surfactants, materials capable of forming crystalline inclusion complexes or other suitable molecules known to those skilled in the art to have properties to change solubility characteristics or to augment the tissue penetration previously described. Plasticizers well-known to those skilled in the art may be incorporated to alter the physical properties of the polymer carrier.

The therapeutic agents or medicaments 40 employed can be compounds that inhibit cellular proliferation such as paclitaxel, paclitaxel derivatives, rapamycin (also known as sirolimus) and rapamycin derivative.

To perform as a polymer coated device for high dose passive diffusional therapeutic agent or medicament delivery, the distal expansion member will be coated as described in more detail below.

A precise volume of a viscous polymer solution, either by itself or mixed with medicaments 43, 47 with or without solubility-altering excipients 39 or tissue permeation enhancers, is pumped through a slot into a coating groove as the device is rotated to evenly coat the mesh. A single layer or multiple layers of viscous polymer containing medicaments 47 with or without excipients 39 are then deposited onto the catheter mesh surface.

Other coating methods may also be employed to deposit a uniform and defined layer of polymer solution onto the surface of the catheter mesh. Conventional coating technology is well known to those skilled in the art or can be determined in standard references.

The coated catheter is then dried in air with or without heat either between coats or after the final coat. For the present invention it is preferred that several coats without medicament be applied and dried to be followed by one or more final coats with a very high medicament to polymer 48 solids ratio.

Additional layers serving different purposes may be added. The additional layers of polymer may be of the same kind, or of a different kind, of polymers depending on the desired application For example, a very thin layer of hydrogel may be initially applied to the catheter mesh surface to promote adhesion. Alternatively, a secondary layer formed of the same or a different polymer may be applied to cover the primary coating that contains the drugs or medicaments 40 in a manner similar to that described above. This coating may contain zero or more additional drugs or medicaments 40 and zero or more excipients 39. Depending on application requirements, multiple layers of polymer coating may be used.

Preferably, the coated expansion member 35 should have a diameter that is only slightly greater than the tubular member 12, as for example by 1.0-2.3 millimeters. The first and second collars 41 and 42 also have been sized so they only have a diameter that is slightly greater than the outer diameter of the outer flexible elongate tubular member 12. To bring the cylindrical expansion member 31 to its lowest configuration, the linear movement mechanism 46 has been adjusted so that there is a maximum spacing between the distal extremity 23 of the inner flexible elongate tubular member 21 and the distal extremity 14 of the outer flexible elongate tubular member 12. In this position of the expansion member 31, the flexible elongate elements 36 cross each other at nearly right angles so that the interstices or openings 37 therebetween are elongated with respect to the longitudinal axis.

The polymer coated device for passive diffusional drug delivery 11 is then inserted into a guiding catheter (not shown) typically used in such a procedure and introduced into the femoral artery and having its distal extremity in engagement with the ostium of the selected coronary artery.

The guide wire 26 is then advanced in a conventional manner by the physician undertaking the procedure and is advanced into the vessel containing a stenosis. The progress of the distal extremity of the guide wire 26 is observed fluoroscopically and is advanced until its distal extremity extends distally of the stenosis. With the expansion member 31 in its diametrically contracted position and the medicament containing polymer or polymer with therapeutic agent coated thereonis advanced over the guide wire 26 until the distal end is centered within the region of interest.

After the polymer-coated cylindrical expansion member 35 is in a desired position in the stenosis, the cylindrical expansion member 35 is expanded from its diametrically contracted position to an expanded position by moving the distal extremities 14 and 23 closer to each other by operation of the screw mechanism 46. This can be accomplished by holding one distal extremity stationary and moving the other distal extremity towards it or by moving both distal extremities closer to each other simultaneously.

When the polymer coated distal cylindrical expansion member 35 is fully expanded it is almost a solid tubular mass which has significant radial strength to fully expand a stenosis or secure intimate pressurized contact with the vessel walls. Since the expansion member is coated with a polymer with medicament within and thereon the therapeutic agent or medicament can be delivered to the vessel during the time of device expansion while blood is permitted to flow unobstructed to the distal vessel.

After delivery of the medicaments or therapeutic agent to the lesion has been carried out for an appropriate length of time, the expansion member 31 can be returned from its expanded position to a contracted position. After the expansion member 31 has been reduced to its contracted or minimum diameter, the polymer coated device for drug delivery 11 can be moved to another desired treatment site or removed along with the guide wire 26 after which the guiding catheter (not shown) can be removed and the puncture site leading to the femoral artery closed in a conventional manner.

Although, the procedure hereinbefore described was for treatment of a single stenosis or region of interest, it should be appreciated that if desired during the same time another stenosis or region of interest need be treated, the catheter may be advanced to this second area of interest and the procedure repeated. Alternatively, another polymer coated device for drug delivery 11 may be re-inserted in the same or other vessels or regions of interest of the patient and can be treated in a similar manner.

Described below are some examples of experiments conducted using the present invention.

EXAMPLE 1 Local Delivery of Paclitaxel

1a Multi-Step Coating of Mesh Catheters

Metal mesh catheters were coated in several steps with different polymer compositions to generate suitable physical properties and a sufficiently high surface concentration of paclitaxel for in-vivo passive diffusional delivery in pigs.

The catheter mesh was first coated in three coating steps by rotation in a measured volume of a 4% w/w solution of a hydrophilic polyurethane such as Hydromed D3 (CardioTech International, Inc., Woburn, Mass.) in 85/15, w/w Ethanol/H2O. After each coating step each device was dried for an hour at room temperature in a high ventilation situation such as a chemical fume hood. The thrice coated meshes are dried overnight in an oven at 40° C.

The meshes are then final-coated in two steps using the same method but a different composition. For this procedure the same polymer is dissolved in tetrahydrofuran (THF) on a stirring hotplate at 60° C. to reach a final concentration of 4% w/w. When the polymer is dissolved, paclitaxel is added so that the paclitaxel to polymer ratio is 82/18 w/w and the solution vortexed until the paclitaxel is dissolved. One gram of toluene is added to the mixture for each 3 grams of THF and two coats of the resulting mix are applied directly to the catheter and dried in the oven at 40° C.

At the time of testing in vitro or vivo the catheter is first wetted for one minute in phosphate buffered saline and flexed. At this time the essentially transparent coating becomes opaque white, the paclitaxel apparently crystallizing at the surface.

1b Chemical Assay for Paclitaxel in Catheters

Catheters or collected distal expansion meshes are air or oven dried (˜37° C.) before beginning drug extraction to determine total drug content. Each mesh was placed in an identified 12 mm by 75 mm disposable test tube. Slowly apply 75 microliters of chloroform was slowly applied to the mesh by means of a syringe or pipette. The test tube is covered with aluminum foil to minimize evaporation of the solvent and thus maximize swelling of the polymer. The swelling should be allowed for at least 15 minutes.

After the polymer-swelling interval a 5 ml aliquot of ethanol is added at once by means of pipette. The mesh is used to stir the solution and after a few minutes the mesh is withdrawn and by flicking it carefully against the side to the volume within the mesh is drained and the central lumen space is refilled by re-immersion with flicking, noting the bubbles that indicate refilling. This may be done several times over a period of 30 minutes or more of extraction.

After the extraction interval is complete the mesh is carefully drained into a 50 ml screw top scintillation vial and the remaining contents of the test tube poured into the vial for submission for filtration to remove particulates if any prior to reverse phase HPLC analysis using aqueous acetonitrile as the mobile phase.

Measurement of the concentration in the solution is by means of peak integration using a standard contemporary HPLC calibration curve and the total mass of paclitaxel is calculated based upon the 5 ml extraction volume.

Analytical method development indicated that a single extraction was sufficiently efficient in that less than 1% of the drug could be extracted in a second, identical extraction.

Example Results

Note: the following results were obtained by methylene chloride polymer swelling to demonstrate content analysis method and consistency of the roll-coating method described. Paclitaxel Paclitaxel Sample (μg/ml) (μg) DS2 478 1,432 DS3 495 1,482 DS4 539 1,615 DS5 497 1,489 DS6 529 1,583 Mean 508 1,520 St. Dev. 25.41 76.07 1c Ex Vivo Paclitaxel Delivery

In an experiment to measure the amount of paclitaxel released, the catheter was placed in an isolated pig blood vessel and expanded against the vessel walls for 10 minutes. Then the catheter was removed and the vessel perfused at 80-100 ml per minute for one hour. The tissue was then analyzed for paclitaxel concentration.

1d In Vivo Paclitaxel Delivery in the Pig

In an experiment to measure the amount of paclitaxel released, the catheter was inserted into a coronary blood vessel of an anesthetized pig and expanded against the vessel walls. Domestic pigs weighing 30-40 kg were anesthetized in the usual manner. An introducer sheath was placed into the femoral artery. A guide catheter was then advanced to the target artery. The artery was then instrumented with a 0.014 inch guidewire. The passive diffusion drug delivery catheter was advanced over the guidewire to the delivery site. The catheter was then expanded for ten minutes. Distal blood flow to the artery was documented angiographically. After the delivery period, all equipment was removed and the animal was recovered. The animal was killed at a later predetermined time by injection of an overdose of barbiturate. The pig was sacrificed after 1, 24 48 or 72 hours and the treated blood vessel harvested and either analyzed immediately or frozen on dry ice for quantitative chemical assay of paclitaxel.

1e Paclitaxel Tissue Assay

After weighing in polystyrene tubes, tissues are homogenized in 4% Bovine Serum Albumin (BSA) (w/v in water) using an Omni International TH 115 tissue homogenizer. About 1 ml of BSA solution was used per 0.1-0.2 g of tissue.

The solution was acidified to litmus indicator with 1N hydrochloric acid. An extraction was performed by adding diethyl ether (2 ml) to each tube. The tubes were vortexed for 1 minute, followed by centrifugation at 2000 rpm for 5 min. Next, the aqueous layer was frozen in ethanol-solid carbon dioxide and the organic layer was decanted into a clean glass tube. The aqueous layer was thawed, checked to confirm acidity, followed by the addition of HCl if necessary, and the extraction procedure was repeated once again. The diethyl ether fractions were combined and evaporated overnight.

The residue was reconstituted in 500/μul of water/acetonitrile (50/50) and 0.1% trifluoroacetic acid. The solution was filtered and injected into an HPLC an for analysis (column: C18 Hypersil ODS [Agilent], mobile phase: acetonitrile 47%/water 53%, trifluoroacetic acid, 0.1%), flow rate of 1 ml/min, with an ultraviolet detector set at 204 256 nm. As an example, arterial tissue concentrations of paclitaxel measured 24 hours following delivery ranged from less than 1 to greater than 90 ug per gram tissue. 

1. An apparatus for delivering a therapeutic agent or medicament comprising: a catheter with an expandable portion having a surface adapted to contract a vessel wall when in an expanded condition, said expandable portion having a perfusion means therein to allow blood flow through the expandable portion; a first flexible polymer coating on the expandable portion; a second coating on the expandable portion, disposed substantially over the first flexible polymer, said second coating having a therapeutic agent or medicament to polymer ratio of at least 4 to 1 by weight.
 2. An apparatus as recited in claim 1 further comprising one or more excipients interacting with said polymer incorporating one or more therapeutic agents or medicaments.
 3. An apparatus as recited in claim 1, wherein said catheter with polymer retaining a high concentration therapeutic agent or medicament will function to release the medicaments from the polymer into tissue by diffusional means.
 4. An apparatus as recited in claim 1, wherein said catheter with polymer carrying a therapeutic agent or medicament will function to deliver the medicaments into target tissues of said vascular segment or body passageway by diffusional means because of high concentration at the surface.
 5. An apparatus as recited in claim 1, wherein said therapeutic agent or medicament is a compound that inhibits cellular proliferation, paclitaxel and paclitaxel derivatives or rapamycin and rapamycin derivatives, and any combinations thereof.
 6. An apparatus as recited in claim 1, wherein said therapeutic agent or medicament will migrate into target tissues when exposed to a high concentration of the drug at the surface.
 7. An apparatus as recited in claim 1, further comprising a solvent that rapidly evaporates and exposes a crystalline therapeutic agent or medicament.
 8. An apparatus as recited in claim 1, wherein said therapeutic agent or medicaments crystallize and become exposed on the surface of said expansion member.
 9. An apparatus as recited in claim 1, wherein said therapeutic agent or medicament is a combination of one or more medicaments.
 10. An apparatus as recited in claim 1, wherein said catheter coated with a therapeutic agent or medicament and polymer matrix is an over-the wire design.
 11. An apparatus as recited in claim 1, wherein said catheter coated with a therapeutic agent or medicament and polymer matrix employs a rapid exchange design.
 12. An apparatus as recited in claim 1 further comprised by a first contracted configuration and a second expanded configuration wherein said expandable distal end is adapted to allow blood perfusion while said expandable distal is in either in said first contracted configuration or in said second expanded configuration.
 13. An apparatus as recited in claim 1, further comprising said first polymer having a low drug content such that the flexibility of the first flexible polymer is not substantially degraded.
 14. An apparatus as recited in claim 1 wherein said apparatus is coated with a first flexible polymer without a medicament or excipient, said first flexible polymer is substantially coated with a very high medicament concentration of a solvent that has a rate of evaporation to promote high drug deposition at the surface.
 15. A drug delivery device comprising; a catheter having an expandable portion having a surface adapted to substantially contact a vessel wall when in a expanded condition; said expandable portion have a perfusion means therein to allow blood flow through the expandable position; and paclitaxel or paclitaxel derivative disposed on the surface of the expandable portion, said coated expandable portion having some crystalline paclitaxel or paclitaxel derivative disposed on the surface said coated expandable portion.
 16. A drug delivery device comprising; a catheter having an expandable portion having a surface adapted to substantially contact a vessel wall when in a expanded condition; said expandable portion have a perfusion means therein to allow blood flow through the expandable position; and rapamycin or rapamycin derivative disposed on the surface of the expandable portion, said coated expandable portion having some crystalline rapamycin or rapamycin derivative disposed on the surface said coated expandable portion.
 17. A method for introducing encapsulated medicaments into cells of a patient, comprising the steps of: selecting as an elongated catheter a substantially cylindrical shaped expansion member located on a distal end, said expansion member having a first end and a second end, said first end being a distance from said second end, an altering means engagable to said first end and said second end of said expansion member for altering said first distance therebetween to move said expansion member between a first configuration wherein said expansion member is characterized by a first diameter and a second configuration wherein said expansion member is characterized by a second diameter, said second diameter being greater than said first diameter; said expansion member having at least one coating, an outer coating having a therapeutic agent or medicament to polymer ratio of at least 4 to 1 by weight; locating said catheter into a selected blood vessel or other lumenal physiological structure of a patient; expanding said cylindrical expansion member wherein a portion of said cylindrical expansion member contacts the vessel wall at a predetermined location;
 18. A method for delivering a medicament to an obstruction in a body passageway which comprises the steps of: advancing a polymer coated device for diffusional mediated drug delivery to a predetermined site with a body passageway, said catheter having an substantially cylindrical expansion member coated with a high concentration of a therapeutic agent or medicament, said expansion member being moveable between a first contracted configuration wherein said expansion member is defined by a first dimension extending in a radial direction, and a second expanded configuration wherein said member is defined by a second dimension extending in said radial direction; applying a force on said coated expansion member in an axial direction to move said expansion member between said first contracted configuration to said second expanded configuration wherein said expansion member dilates said obstruction or body passageway and delivers the therapeutic agent or medicament firmly against said obstruction or body passageway.
 19. A method as recited in claim 18 which further comprises the step of positioning a guidewire in the body passageway, and wherein said advancing step is accomplished by threading said expansion member over said guidewire.
 20. A method as recited in claim 18 which further comprises the step of allowing said expansion member to be in said second expanded configuration for a predetermined period of time after the dilatation step to further expose said obstruction to the medicament.
 21. A method for dilating and delivering a medicament to an obstruction in a body passageway which comprises the steps of: advancing a polymer coated device for diffusion mediated drug delivery to a predetermined site within a body passageway, said device having an expansion member coated with a polymer and a crystalline medicament, said expansion member being moveable between a first contracted configuration wherein said member is defined by a first dimension extending in a radial direction, and a second expanded configuration wherein said member is defined by a second dimension extending in said radial direction; applying a force on said expansion member in an axial direction to move said expansion member between said first contracted configuration to said second expanded configuration wherein said obstruction is dilated; applying a pressure against the tissue to deliver the crystalline medicament into said obstruction or body passageway.
 22. A method as recited in claim 21 which further comprises the step of positioning a guidewire in the body passageway, and wherein said advancing step is accomplished by threading said catheter over said guidewire.
 23. A method as recited in claim 21 which further comprises the step of allowing said expansion member to be in said second expanded configuration for a predetermined period of time after the dilatation step to further expose said obstruction to the medicament.
 24. An apparatus for delivering a medicament to an obstruction within a vascular segment or a body passageway which comprises: a catheter with an expandable mechanical distal end; said distal end incorporating a polymer carrying one or more medicaments at high surface concentrations, a medicament formulation that does not release significant drug into the systemic circulation, and a medicament formulation and polymer that upon wetting and flexing the apparatus causes a portion of the medicament formulation to crystallize and to become exposed at the surface of the expandable mechanical distal end and increase exposure to the tissue.
 25. An apparatus as recited in claim 24, wherein said catheter with polymer carrying a therapeutic agent or medicament will function to release the medicaments from the polymer by diffusional means.
 26. An apparatus as recited in claim 24, wherein said catheter with polymer encapsulating a therapeutic agent or medicament will function to deliver the medicaments into target tissues of said vascular segment or body passageway by diffusional means.
 27. An apparatus as recited in claim 24, wherein said therapeutic agent or medicament is a compound that inhibits cellular proliferation, paclitaxel and paclitaxel derivatives or rapamycin and rapamycin derivatives, and any combinations thereof.
 28. An apparatus as recited in claim 24, wherein said polymer carried agent or medicament is a combination of one or more medicaments.
 29. An apparatus as recited in claim 24, wherein said catheter with polymer carrying a therapeutic agent or medicament is an over-the wire design.
 30. An apparatus as recited in claim 24, wherein said catheter with polymer carrying a therapeutic agent or medicament employs a rapid exchange design.
 31. An apparatus as recited in claim 24, further comprised by a first contracted configuration and a second expanded configuration wherein said expandable distal end is adapted to allow blood perfusion while said expandable distal end is either in said first contracted configuration or in said second expanded configuration.
 32. An apparatus as recited in claim 24, wherein said expandable distal end can perform dilatation and drug delivery while simultaneously allow blood perfusion.
 33. An apparatus as recited in claim 24, wherein said crystalline medicament formulation is paclitaxel or a paclitaxel derivative.
 34. An apparatus as recited in claim 24, wherein said crystalline medicament formulation is rapamycin or a rapamycin derivative.
 35. A method for coated a stent with multiple coatings: employing a water based solvent to incorporate one or more medicaments into a polymer to comprise a first base coating; coating a portion of the distal expandable end of a drug delivery catheter with said first base coating; employing an organic based solvent to incorporate one or more medicament into a polymer to comprise a second top coating, said second top coating having medicament to polymer ratio of at least 4 to 1 by weight; coating said second top coating substantially over said first base coating.
 36. A method as recited in claim 35, further comprising that said water based solvent is H₂O, ethanol or any alcohol derivative, or any combination of H₂O, ethanol or any alcohol derivative thereof.
 37. A method as recited in claim 35, further comprising that said organic based solvent is tetrahydrofuran or toluene, or any combination of tetrahydorfuran and toluene thereof. 